The goal of the research effort is to develop an understanding of biologically important molecules in solution to elucidate their mechanism of action. In this project an investigation is proposed of the structural and dynamic properties of the enzyme dihydrofolate reductase from E. coli. This is an important enzyme involved in metabolic control and synthesis of important precursors in biosynthesis. For this reason, and its wide distribution it has been a target for drug design. Several anti-dihydrofolate reductase drugs are already in use as antibacterial and anticancer agents. The work here will explore the drug - enzyme interactions to improve the rational design of inhibitors for this enzyme. Nuclear magnetic resonance is the most effective technique for such studies, but this protein is a challenge to solution NMR because of its size. New 3-dimensional NMR techniques with isotopically labeled protein show a great deal of promise in the solution conformational analysis. This grant will support research at one of the leading laboratories where the new approaches are being developed and applied to facilitate the use of the methodologies on this enzyme.